Human tumor virus infection and immune control in vivo
Session type: Oral
Primary infection with the human oncogenic Epstein Barr virus (EBV) can result in infectious mononucleosis (IM), a self-limiting disease caused by massive lymphocyte expansion, which predisposes for the development of distinct EBV- associated lymphomas. It remains unclear why some individuals experience this symptomatic primary EBV infection, while the majority acquires the virus asymptomatically.
Using a mouse model with reconstituted human immune system components, we could show that depletion of human natural killer (NK) cells enhances IM symptoms and promotes EBV-associated tumorigenesis, mainly due to loss of immune control over lytic EBV infection. These data suggest that failure of innate immune control by human NK cells augments symptomatic lytic EBV infection, which drives lymphocyte expansion and predisposes for EBV-associated malignancies. These human NK cells carry inhibitory killer cell immunoglobulin-like receptors (KIRs), recognizing distinct HLA molecules. NK cells with KIRs for self-HLA molecules acquire superior cytotoxicity against HLA negative tumor cells during education for improved missing-self recognition. We could show that co-reconstitution of two KIR-ligand mismatched human immune system compartments in mice does not alter the frequency of KIR expressing NK cells, but their education.
NK cell education is diminished for KIRs, whose cognate HLA molecules are lacking on leucocytes that reconstitute in parallel in the same mice. This change in NK cell education in mixed human donor reconstituted mice is functionally relevant, because it improves NK cell mediated immune control of Epstein Barr virus infection. Thus, leucocytes lacking cognate HLA ligands can disarm KIR positive NK cells for improved immune control of a human gamma-herpesvirus.